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Outcomes Associated With HER2DX ERBB2 mRNA Expression in Patients With Advanced HER2+ MBC Treated With T-DM1
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- This study evaluated the HER2DX variables in patients with advanced HER2+ metastatic breast cancer (MBC) treated with trastuzumab emtansine (T-DM1). The results demonstrated that ERBB2 mRNA expression, as measured using the standardized HER2DX assay, was associated with response to T-DM1. The overall response rate was higher in the ERBB2-high groups compared with the ERBB2-medium or ERBB2-low groups. ERBB2 mRNA expression was significantly associated with better progression-free survival and overall survival (OS) outcomes.
- HER2DX risk and immunoglobulin signature scores were significantly associated with OS from the time of diagnosis. The standardized HER2DX genomic assay has potential predictive and prognostic utility in patients with advanced HER2+ MBC treated with T-DM1.
abstract
This abstract is available on the publisher's site.
Access this abstract nowIn advanced HER2-positive (HER2+) breast cancer (BC), the new antibody-drug conjugate trastuzumab deruxtecan (T-DXd) is more effective compared to trastuzumab emtansine (T-DM1). However, T-DXd can have significant toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if pre-established levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29% and 56%, respectively (P<.001). ERBB2 mRNA was significantly associated with better progression-free survival (p = 0.002) and overall survival (OS; P = 0.02). These findings were independent of HER2 IHC levels, hormone receptor, age, brain metastasis and line of therapy. The HER2DX risk-score (P=.04) and the immunoglobulin (IGG) signature (P=.04) were significantly associated with OS since diagnosis. HER2DX provides prognostic and predictive information following T-DM1 in advanced HER2+ BC.
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HER2DX ERBB2 mRNA expression in advanced HER2-positive breast cancer treated with T-DM1
J. Natl. Cancer Inst 2022 Dec 28;[EPub Ahead of Print], F Brasó-Maristany, G Griguolo, N Chic, T Pascual, L Paré, J Maues, P Galván, MV Dieci, F Miglietta, T Giarratano, O Martínez-Sáez, M Marín-Aguilera, F Schettini, B Conte, L Angelats, M Vidal, B Adamo, M Muñoz, E Sanfeliu, B González, A Vivancos, P Villagrasa, JS Parker, CM Perou, P Conte, A Prat, V GuarneriFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The development of several novel HER2-targeted therapies has resulted in significant improvement in the outcomes of patients with HER2+ metastatic breast cancer. Trastuzumab emtansine (T-DM1) was the first antibody–drug conjugate (ADC) approved for the treatment of breast cancer, involving trastuzumab antibody chemically linked to the chemotherapy drug emtansine (also known as DM1). One of the most challenging aspects of ADC treatment in solid tumors is the heterogeneous expression of target antigens in the metastatic tumor tissue. The bystander effect somewhat overcomes this issue, owing to the cytotoxic effects on the cells surrounding the tumor cells, including those with a heterogeneous expression of the target. Not all ADCs have demonstrated this bystander effect. For example, the activity of T-DM1 is dependent on the expression of HER2 in the tumor tissue. However, biomarkers are needed to guide the optimal sequencing beyond HER2 status. HER2DX assay measures the expression of 27 genes from formalin-fixed and paraffin-embedded tumor biopsies and evaluates the following biological processes: immune infiltration, luminal differentiation, tumor cell proliferation, and HER2 amplicon expression. In this study, the authors evaluated if pre-established levels of ERBB2 mRNA expression based on the HER2DX standardized assay were associated with the response and survival outcomes of patients following treatment with T-DM1. The assay provided prognostic and predictive information on patients treated with T-DM1 for advanced breast cancer. These findings, if further validated (especially in patients pretreated with trastuzumab deruxtecan), could be useful in identifying patients who are most likely to benefit from T-DM1 and in better optimizing the sequencing of therapies.